All aspects of the proposed work pertain to the thyroid axis,providing thematic unity. Operational cohesion is provided by the participation and leadership of the applicant, by his experience, and by his commitment to mentorship. Clinical studies are guided in part by the observation that changes in thyroid status,especially toward hypothyroidism, are common and by the notion that such changes, even when slight, may impair CNS function. Study One is addressed to patients with Graves' disease, who are assessed in several ways when hyperthyroid (from illness), when hypothyroid (from radioiodine treatment), and when euthyroid (from hormone replacement). In Study Two the notions are examined: that patients coming for ECT may have been inadvertently "selected" for subclinical hypothyroidism; that ECT thus does them "special" damage, because it, like hypothyroidism, impairs memory. Does administered thyroid hormone protect them? Study Three goes directly to the question of subclinical hypothyroidism. What is its prevalence? Do such patients profit from treatment with a thyroid hormone? Study Four seeks to assess the extent to which TRH will offset effects of common sedatives. In Study Five children with a learning disorder are assessed for the nature and severity of their disorder and for subtle changes in thyroid status. Four animal studies are proposed, each resonating with one or another clinical study. In Study One the role of thyroid hormones in regulating the uptake of calcium by brain neurons is measured. We have found that hypothyroidism reduces depolarization-induced calcium ptake. In Study Two the complex relationships in rats between alcohol intake and thyroid state are examined, including an analog of the now-classical clinical finding, TSH blunting in response to administered TRH. Study Three examines the effects of psychotropic drugs, including common sedatives, on TRH binding in brain. Study Four takes as its dependent variable the uptake by brain neurons of thyroid hormones (see uptake of calcium, above). How do drugs affect it? We have confirmed the finding of Dratman that desmethylimi- pramine reduces thyroxine uptake. Do antidepressants make the brain hypothyroid?